In ferrets with hyperadrenocorticism, does use of deslorelin acetate implants compared to adrenalectomy result in a superior prognosis?

a Knowledge Summary by

Megan Ballman BVMSci(Hons) fCMgr ACMI MRCVS ^1*

¹School of Veterinary Medicine, Daphne Jackson Road, University of Surrey, Guildford, Surrey, GU2 7AL
^*Corresponding Author (megan@scottveterinaryclinic.co.uk)

Clinical scenario

A client presents their female spayed ferret as she has become symmetrically alopecic, has vulvar swelling and is showing sexual behaviour. You recognise this presentation as hyperadrenocorticism (HAC), also known as ferret adrenocortical disease (ACD). The clinical disease seen in ferrets is not the same as Cushing’s disease in dogs, when cortisol levels are elevated due to a pituitary tumor. Neoplasms of the adrenal cortex have the potential to overproduce steroids (glucocorticoids, mineralcorticoids, androgens) of the adrenal glands, leading to the syndrome of HAC. In ferrets, adrenal cortex neoplasms usually overproduce one or more of the sex hormones oestradiol, androstenedione, or 17α-hydroxyprogesterone and in contrast to Cushing’s disease, the contralateral adrenal gland usually does not atrophy (Chen, 2010). Following diagnosis based on these clinical signs and further testing, you consider your treatment options.

Whilst adrenalectomy has been a mainstay treatment for HAC, you are aware of its limitations. Research into the use of deslorelin acetate implants, a synthetic analogue of gonadorelin and sold under the brand name Suprelorin®, has led this medical therapy to become more popular in non-surgical candidates. You want to know whether there is evidence that treating this ferret with a deslorelin acetate implant compared to adrenalectomy surgery will result in a superior prognosis.

The evidence

The literature search yielded one relevant paper (Lennox & Wagner, 2012) that found that treatment with deslorelin acetate implants resulted in a longer average time to recurrence of clinical signs and a lower mortality rate than adrenalectomy. However, this study has limitations; it is a retrospective study so has weak evidentiary value and as a cohort study there is likely to be confounding factors. Furthermore, the small sample size affects reliability of results and because no statistical analysis was carried out, the results cannot be assumed to be clinically significant. Therefore, the strength of evidence for this PICO is very low and therefore further studies are required before any recommendations can be made.

Summary of the evidence

Appraisal, application and reflection

One paper (Lennox & Wagner, 2012) was found to directly address the topic of this Knowledge Summary, and this was a retrospective cohort study. Whilst there are multiple papers about the prognosis of either surgery (Swiderski et al., 2008; and Weiss et al., 1999) or deslorelin acetate implants (Wagner et al., 2005; and Wagner et al., 2009) for treatment of ferret HAC, the study by Lennox & Wagner (2012) was the only paper yielded from the literature search to compare the outcomes of both and was therefore the only study deemed to have evidence worthy of inclusion.

Medical treatment for ferret HAC is aimed at controlling clinical signs through hormone manipulation and is typically used for non-surgical candidates or for treating recurrence of clinical signs after an adrenalectomy (Chen, 2010). The benefits include a non-invasive approach and few side effects, however, medical therapies have not shown to directly affect the adrenal tumour itself and autonomous production of steroids by the adrenal gland may occur over time, resulting in a loss of efficacy of the implant and recurrence of clinical signs (Shoemaker & van Zeeland, 2021). In comparison, the limitations of adrenalectomy are the challenging surgical technique and risk of complications, such as deterioration or death of compromised patients, and recurrence (Shoemaker, 2017).

Lennox & Wagner (2012) reviewed the medical records of two groups of ferrets exhibiting overt clinical signs consistent with HAC, that either received an adrenalectomy or subcutaneous 4.7 mg deslorelin acetate implants alone, to identify if there was a difference in clinical outcomes. However, authors failed to carry out statistical analysis of their results and so the clinical significance of their findings is questionable.

Firstly, the study by Lennox & Wagner (2012) found that post-treatment, the medical group had superior outcomes, including numerically a longer time to recurrence of clinical signs than the surgical group (16.5 months vs 13.6 months). This is similar to a study in which 30 ferrets with HAC were given 4.7 mg deslorelin acetate implants and the average time to return of clinical signs was reported as 17.6 months (Wagner et al., 2009). Interestingly, the time to relapse was quite variable, both in this study (8–30 months) and in the reviewed study (3–30 months), therefore inter-species variation in clinical response should be acknowledged for this treatment. Nevertheless, in the paper by Lennox & Wagner (2012), the authors acknowledged that ‘time to return to clinical signs’ may not correlate with progression of disease, so this outcome may not be a true assessment of prognosis. As follow-up methods were not described, the results may be unreliable especially if the assessment of clinical signs was carried out by the owner. Furthermore, loss to follow-up can bias the data and as this is a subjective variable there may be observer bias.

Lennox & Wagner (2012) found that the medical group also had a lower mortality rate (5.6% vs 0%) which could imply better patient safety. Nevertheless, a two-tailed Fisher’s exact test indicates a non-significant difference (P = 0.276) between mortality in the surgical group, with a prevalence of 5.6% (3/54), compared to the medical group, with a prevalence of 0% (0/35). In addition, as cause of death in the surgical group was not confirmed by necropsy, direct causation cannot be proved. Comparatively, a retrospective study by Swiderski et al. (2008) looked at long-term outcomes of surgical intervention in 130 ferrets and found a 98% 1 year survival and 70% 5 year survival, which indicates that surgical treatment has a good prognosis. However, 14.3% ferrets that underwent bilateral adrenalectomy developed signs of hypoadrenocorticism (Swiderski et al., 2008), a negative outcome that is not reported with deslorelin acetate implants as they do not affect the adrenal tumour itself (Morrisey, 2013).

Finally, in the paper by Lennox & Wagner (2012) it is difficult to interpret ‘no response to treatment’ as there were mistakes in the data and a lack of clarity in reporting the findings. For example, the main text leads the reader to think that the sample size for this outcome was 28 rather than 51. This study stated that all ferrets in the medical group responded, a superior outcome to surgery, however a two-tailed Fisher’s exact test shows this outcome was not significant (P = 0.267) between the surgical group (3/51) and the medical group (0/35). On the other hand, there are rare reports in the literature of non-response to hormonal therapy. For example, a case study by Brezina et al. (2019) reported that a ferret showed no improvement after 4 months following 9.4 mg deslorelin acetate implantation. As a result, adrenalectomy was performed resulting in complete resolution of clinical signs, which demonstrates that this therapeutic option may be preferable in some cases. In fact, in the article by Lennox & Wagner (2012) they state that since preparing the paper, both authors identified at least one patient that did not respond to the deslorelin acetate implant. Nevertheless, there are currently no studies reporting on prospectively identifying which ferrets will not respond to implants.

Interestingly, the author found a study that reviewed deslorelin acetate implants by Wagner et al. (2005), where the duration of clinical effects in ferrets with HAC that had previously undergone adrenalectomy was almost 4 months longer than that of ferrets with no previous surgery. The difference in time to clinical relapse between adrenalectomised and non-adrenalectomised ferrets was significant (P<0.05) and so this study suggests the need for further research into the benefits of combining these therapies.

In conclusion, whilst the pilot study by Lennox & Wagner (2012) proposes that deslorelin acetate implants have good safety, efficacy and some advantages over adrenalectomy, there is currently insufficient evidence to prove that this medical treatment leads to a superior prognosis than adrenalectomy in ferrets with HAC. Undoubtedly, further experimental studies, ideally randomised control trials, which directly compare these options would be necessary before conclusions can be made.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts on OVID Platform [1985–2021] PubMed via the NCBI Interface [1938–2021] Web of Science All Databases [1998–2021]
Search strategy:	(ferret* OR mustel*) AND (adrenal* OR adreno* OR hyperadren* OR cushing*) AND (“Deslorelin acetate” OR Deslorelin OR Ovuplant OR SucroMate OR Suprelorin OR “GnRH analogue” OR “GnRH agonist”) AND (surger* OR adrenalectom*)
Dates searches performed:	22 May 2021

Exclusion / Inclusion Criteria
Exclusion:	Not relevant to PICO. No direct comparison. No English publication available.
Inclusion:	Studies in English that are relevant to the PICO and compare outcomes of surgery versus deslorelin acetate implants.

Search Outcome
Database	Number of results	Excluded – Not relevant to PICO	Excluded – Non-comparative	Excluded – Non-English publication	Total relevant papers
CAB Abstracts	16	8	6	1	1
PubMed	2	0	2	0	0
Web of Science	12	6	5	0	1
Total relevant papers when duplicates removed					1

The authors declare no conflicts of interest.

The author would like to thank Karen Pickering for her support in this work.

1. Brezina, T., Thöle, M., Klotz, D., Herder, V. & Fehr, M. (2019). Surgical therapy of a non-deselin-responsive adrenal gland adenocarcinoma in a four-year-old ferret (Mustela putorius furo). Kleintierpraxis. 64(5), 280–290. DOI: https://doi.org/10.2377/0023-2076-64-280
2. Chen, S. (2010). Advanced Diagnostic Approaches and Current Medical Management of Insulinomas and Adrenocortical Disease in Ferrets (Mustela putorius furo). Veterinary Clinics of North America: Exotic Animal Practice. 13(3), pp.439–452. DOI: https://doi.org/10.1016/j.cvex.2010.05.002
3. Lennox, A. & Wagner, R. (2012). Comparison of 4.7-mg Deslorelin Implants and Surgery for the Treatment of Adrenocortical Disease in Ferrets. Journal of Exotic Pet Medicine. 21(4), pp.332–335. DOI: https://doi.org/10.1053/j.jepm.2012.09.001
4. Schoemaker, N. (2017). Ferret Oncology: Diseases, Diagnostics, and Therapeutics. Veterinary Clinics of North America: Exotic Animal Practice. 20(1), 183–208. DOI: https://doi.org/10.1016/j.cvex.2016.07.004
5. Shoemaker, N. & van Zeeland, Y. R. A. (2021). Endocrine Disorders Of Ferrets. [online] MSD Veterinary Manual. Available at: https://www.msdvetmanual.com/exotic-and-laboratory-animals/ferrets/endocrine-disorders-of-ferrets [Accessed 19 October 2021].
6. Swiderski, J., Seim III, H., MacPhail, C., Campbell, T., Johnston, M. & Monnet, E. (2008). Long-term outcome of domestic ferrets treated surgically for hyperadrenocorticism: 130 cases (1995–2004). Journal of the American Veterinary Medical Association. 232(9), 1338–1343. DOI: http://dx.doi.org/10.2460/javma.232.9.1338
7. Wagner, R., Finkler, M., Fecteau, K. & Trigg, T. (2009). The Treatment of Adrenal Cortical Disease in Ferrets with 4.7-mg Deslorelin Acetate Implants. Journal of Exotic Pet Medicine. 18(2), 146–152. DOI: https://doi.org/10.1053/j.jepm.2008.11.003
8. Wagner, R., Piche, C., Jochle, W. & Oliver, J. (2005). Clinical and endocrine responses to treatment with deslorelin acetate implants in ferrets with adrenocortical disease. American Journal of Veterinary Research. 66(5), 910–914. DOI: https://doi.org/10.2460/ajvr.2005.66.910
9. Weiss, C. A., Williams, B. H., Scott, J. B. & Scott, M. V. (1999). Surgical treatment and long-term outcome of ferrets with bilateral adrenal tumors or adrenal hyperplasia: 56 cases (1994–1997). Journal of the American Veterinary Medical Association. 215(6), 820–823.